Primary results from post hoc analysis of the apollo-b brazilian subpopulation, a phase 3 study of patisiran in patients with transthyretin amyloidosis with cardiomyopathy

BACKGROUND: Transthyretin amyloidosis (ATTR) is a progressive, fatal disease caused by toxic misfolded transthyretin (TTR) amyloid deposits. Patisiran, an RNA interference therapeutic, inhibits synthesis of wild-type and variant TTR and is approved for the treatment of hereditary ATTR with polyneuropathy. OBJECTIVE: Describe efficacy and safety of patisiran in patients from Brazil with ATTR cardiomyopathy (ATTR-CM) via a post hoc subgroup analysis of the global APOLLO-B study (NCT03997383). METHODS: Patients 18­85 years of age with ATTR-CM and heart failure were randomized 1:1 to patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months. Primary endpoint was change from baseline (CFB) in functional capacity (6-minute walk test) at Month 12 for patisiran vs placebo. Secondary endpoints included CFB to Month 12 in health status and quality of life (Kansas City Cardiomyopathy QuestionnaireOverall Summary [KCCQ-OS]). Exploratory endpoints included CFB in cardiac biomarkers and Perugini grade by Tc-99m scintigraphy, the latter assessed in a subset of patients in an imaging study within APOLLO-B. RESULTS: Of 360 patients in APOLLO-B, 42 were from Brazil (patisiran, n=20; placebo, n=22): median (range) age at screening, 73 (51, 85) years; male, 81%; wild-type ATTR, 54.8%. No patients were receiving tafamidis at baseline. Patisiran showed benefit vs placebo in 6-minute walk test (median [95% CI] CFB [meters]: −2.02 [−58.5, 42.9] vs −30.1 [−72.2, 3.5]; HodgesLehmann estimate of median difference [95% CI]: 31.4 [−16.6, 79.4]; Figure 1A) and in KCCQ-OS (least squares mean [SEM] CFB: 9.4 [3.8] vs 2.6 [3.7]; least squares mean difference [SEM]: 6.8 [5.3]; Figure 1B). Death was reported in 0 patisiran patients vs 3 (13.6%) placebo. The ratio of adjusted geometric mean fold-change (patisiran:placebo [95% CI]) was 0.77 (0.57, 1.03) for NT-proBNP and 0.87 (0.68, 1.12) for troponin I. In the imaging subset (n=35), 11/18 (61.1%) patisiran patients improved Perugini grade vs 0/10 placebo at Month 12 (Figure 2). Few patisiran patients experienced serious (8 [40%]) or severe (4 [20%]) adverse events; none were drug related. CONCLUSION: In Brazilian patients with ATTR-CM, potential benefit was observed with patisiran on functional capacity, health status and quality of life, cardiac biomarkers, and Perugini grade, consistent with data from the global APOLLO-B population. The results are descriptive; the study was not powered to detect treatment effects specific to this subgroup.

Impact of patisiran on health status and quality of life in patients with transthyretin cardiac amyloidosis

INTRODUCTION APOLLO-B is a Phase 3 study of patisiran in patients with transthyretin (ATTR) cardiac amyloidosis (NCT03997383), which demonstrated a significant benefit in functional capacity (6-MWT), and health status and quality of life (QoL) (KCCQ-OS) with patisiran vs placebo at Month (M) 12. HYPOTHESIS Patisiran improves health status and QoL in the daily lives of patients with ATTR cardiac amyloidosis vs placebo. METHODS Patients were 18-85 years old with ATTR amyloidosis and a medical history of heart failure (HF) due to ATTR cardiomyopathy, with ≥1 prior hospitalization for HF or current clinical evidence of HF. Patients were randomized (1:1) to intravenous patisiran 0.3 mg/kg or placebo every 3 weeks. These post-hoc analyses evaluated percentage of responders reporting ≥5-point improvement in KCCQ-OS, and change from baseline in 4 KCCQ domains and questions within the domains. RESULTS 359 patients received study drug (patisiran, N=181; placebo, N=178): median age (range), 76 (41, 85) years; male, 89%; wild-type ATTR, 80%; 25% were on tafamidis at baseline. At M12, patisiran showed significant benefit vs placebo in KCCQ-OS (LS mean [SEM] change from baseline: patisiran, 0.30 [1.26]; placebo, -3.41 [1.28]; LS mean [SEM] difference: 3.71 [1.80]; p=0.0397). A ≥ 5-point improvement in KCCQ at M12 was more frequent with patisiran vs placebo (34.1 vs 24.0%: difference [95% CI] 10.1% [0.7, 19.5]). Improvement vs placebo was consistent across domains, with LS mean differences [95% CI] in change from baseline (patisiran - placebo) in Physical Limitations (2.75 [-1.24, 6.74]), Total Symptoms (4.55 [0.75, 8.34]), QoL (4.27 [-0.12, 8.65]), and Social Limitations (2.76 [-2.21, 7.73]). Categorical changes from baseline to M12 demonstrated greater percentages of placebo-treated patients reporting worsening for questions in each domain, including activities requiring greater cardiometabolic demand. In patients with values at baseline and M12, notably greater percentages (>5%) of placebo- vs patisiran-treated patients reported worsening (percent difference; n=placebo/patisiran) for questions related to Walking 1 Block on Level Ground (10%; n=159/162), Frequency and Burden of Dyspnea (9.5% and 7.6%; n=164/170), Frequency of Orthopnea (9.6%; n=163/170), Feeling about Spending the Rest of Their Life with HF the Way It Is Right Now (6.4%; n=164/170), and Intimate Relationships (6.3%; n=88/86). Improvement from baseline was reported by greater percentages (>5%) of patisiran-treated patients (percent difference; n=patisiran/placebo) in Enjoyment of Life Limited Due to HF (12.8%; n=170/164) and Hobbies/Recreational Activities (6.0%; n=141/143). CONCLUSIONS In APOLLO-B, improvements in health status and QoL with patisiran vs placebo were apparent across all 4 KCCQ domains. Greater percentages of patisiran-treated patients had KCCQ-OS improved by ≥ 5 points at M12 and they more often reported improvements in QoL, and ability to enjoy life and perform hobbies/recreational activities. More placebo-treated patients reported worsening in walking on level ground, HF symptoms and QoL.

APOLLO-B, a study of patisiran in patients with transthyretin cardiac amyloidosis: primary long-term results from the open-label extension period

INTRODUCTION: The Phase 3 APOLLO-B study evaluates patisiran in patients (pts) with transthyretin (ATTR) cardiac amyloidosis over a 12-month (M) double-blind (DB) period, followed by an open-label extension (OLE) period when all pts receive patisiran (NCT03997383). Hypothesis: Patisiran provides long-term benefit in pts with ATTR cardiac amyloidosis. Aims: Describe safety and efficacy of patisiran during the APOLLO-B OLE (18M+). METHODS: Pts (18-85 yrs) with ATTR cardiac amyloidosis and heart failure history were randomized 1:1 to patisiran or placebo (pbo). Pts completing DB period were eligible to receive patisiran in the OLE for ≤36M. Results summarized based on DB treatment arm. Exploratory assessments include change from study baseline (CFB) in 6-minute walk test (6MWT), KCCQ-OS, NT-proBNP, and troponin I. RESULTS: In the DB period, 359 pts (pbo n=178; patisiran n=181) received study drug (median [range] age, 76.0 [41, 85] yrs; male, 89%; wtATTR, 80%; tafamidis at baseline, 25%); 334 (93%) entered the OLE. In patisiran arm, M12 and M18 results, respectively, were similar for each endpoint: 6MWT and KCCQ-OS (mean [SEM] CFB) −8.09 [5.73] vs −9.21 [6.04] meters (m) and 0.60 [1.36] vs 0.22 [1.48]; NT-proBNP and troponin I (geometric mean fold-CFB [95%CI]) 1.10 [1.03, 1.17] vs 1.17 [1.07, 1.27] and 1.11 [1.05, 1.18] vs 1.09 [1.01, 1.17]). In pbo arm, patisiran initiation in OLE was associated with a slower rate of worsening or relative stability across endpoints; CFB at M12 vs M18, respectively: 6MWT, −25.43 [5.61] vs −31.08 [5.45] m; KCCQ-OS, −3.41 [1.33] vs −4.02 [1.49]; NT-proBNP, 1.39 [1.28, 1.51] vs 1.53 [1.38, 1.71]; and troponin I, 1.29 [1.21, 1.38] vs 1.21 [1.13, 1.30]. Patisiran had an acceptable safety profile; no new concerns. OLE analyses are ongoing; updated data to be presented. CONCLUSIONS: The M18 results provide evidence that beneficial effects observed in DB period on functional capacity, health status, and quality of life were maintained by continued treatment with patisiran during the OLE. Pbo-treated pts initiating patisiran at M12 showed slowed worsening or stabilization in most endpoints at M18. Early treatment initiation is important: pbo-treated pts did not recover functional capacity or health lost prior to initiating OLE patisiran.

Gene Silencing Therapeutics in Cardiology: A Review Article

Abstract Therapeutics that inhibit enzymes, receptors, ion channels, and cotransporters have long been the mainstay of cardiovascular medicine. Now, oligonucleotide therapeutics offer a modern variation on this paradigm of protein inhibition. Rather than target a protein, however, small interfering ribonucleic acids and antisense oligonucleotides target the messenger RNA (mRNA) from which a protein is translated. Endogenous, cellular mechanisms enable the oligonucleotides to bind a selected sequence on a target mRNA, leading to its degradation. The catalytic nature of the process confers an advantage over the stoichiometric binding of traditional small molecule therapeutics to their respective protein targets. Advances in nucleic acid chemistry and delivery have enabled development of oligonucleotide therapeutics against a wide range of diseases, including hyperlipidemias and hereditary transthyretin-mediated amyloidosis with polyneuropathy. While most of these therapeutics were initially designed for rare diseases, recent clinical trials highlight the potential impact of oligonucleotides on more common forms of cardiovascular disease.

A single misstep in cardiac development explains the co-occurrence of tetralogy of fallot and complete atrioventricular septal defect in Down syndrome.

Tetralogy of Fallot and a complete atrioventricular septal defect are thought to arise by distinct mechanisms, yet their co-occurrence is a recognized association. Analysis of the prevalence of co-occurrence in Down syndrome suggests a common developmental basis. Trisomy 21 may perturb cardiac progenitor cells before they enter the heart tube.